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Astrocytes are highly mechanosensitive cells that play essential roles in maintaining brain homeostasis; however, the molecular mechanisms underlying astrocyte mechanosensation during pathological conditions remain largely unexplored. In this study, we investigated how the expression of the mechanosensitive ion channel Piezo1 in astrocytes is modulated by inflammatory triggers. We found that direct exposure of primary astrocyte cultures to inflammatory stimuli, including lipopolysaccharide (LPS) or oligomeric amyloid\u2010\u03b2 (oA\u03b2), had minimal impact on astrocytic Piezo1 expression. In contrast, when LPS or oA\u03b2 were applied to primary microglia cultures, Piezo1 expression was increased in microglia, and conditioned media from these microglia cultures significantly upregulated Piezo1 expression in astrocytes. We further identified that microglia released pro\u2010inflammatory cytokines (IL\u20101\u03b1, IL\u20101\u03b2, and TNF\u2010\u03b1) that can directly enhance Piezo1 expression and Piezo1\u2010mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling in both rodent and human astrocytes. Microglial depletion in 5xFAD mice consistently and substantially reduced astrocytic Piezo1 expression in\u00a0vivo, supporting the physiological relevance of this microglia\u2013astrocyte signaling axis during pathology. Activation of Piezo1 with Yoda2 did not alter astrocytic inflammatory gene expression under basal conditions but reduced TNF\u2010\u03b1, CCL2, and C3 expression following cytokine pretreatment. Conversely, Piezo1 knockdown increased GFAP expression at baseline and enhanced pro\u2010inflammatory gene expression under cytokine stimulation, indirectly promoting microglial activation. These findings demonstrate that astrocytic Piezo1 expression is regulated by microglia\u2010derived inflammatory signals and plays a context\u2010dependent role in modulating astrocyte reactivity and neuroinflammatory responses.\n                  <\/jats:p>","DOI":"10.1002\/glia.70199","type":"journal-article","created":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T08:02:25Z","timestamp":1785052945000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Microglia\u2013Astrocyte Signaling Axis Regulates Astrocyte Piezo1 Expression and Inflammatory Responses"],"prefix":"10.1002","volume":"74","author":[{"given":"Yanyang","family":"Bai","sequence":"first","affiliation":[{"name":"Research Center for Primate Neuromodulation and Neuroimaging Shenzhen Institute of Advanced Technology, Chinese Academy of Science  Shenzhen Guangdong China"},{"name":"Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun B.","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Wendt","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Towriss","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Djavad Mowafaghian Centre for Brain Health University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ada 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